Is PDE6A p.Ser643Ile (c.1928G>T) pathogenic?

PDE6A p.Ser643Ile (c.1928G>T) is classified Uncertain significance in PDE6A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-31). AlphaMissense: ambiguous (0.465); Ultra-rare (popmax 0.0357%, eas); Associated with Inborn genetic diseases.

What condition is associated with PDE6A p.Ser643Ile (c.1928G>T)?

PDE6A p.Ser643Ile (c.1928G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6A p.Ser643Ile (c.1928G>T) in the general population?

PDE6A p.Ser643Ile (c.1928G>T) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

What do computational predictors say about PDE6A p.Ser643Ile (c.1928G>T)?

AlphaMissense predicts ambiguous (score 0.465) — an in-silico prediction, not a clinical call.

PDE6A p.Ser643Ile

c.1928G>T · rs578228152 · VCV1495131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.465 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.465	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -10.31	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.39	phastCons 0.014
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	19.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,858 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00105% 17/1,612,496 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,804
Remaining individualsnot grpmax-eligible	0.0016%	62,454

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PDE6A
Protein: p.Ser643Ile
Coding: c.1928G>T
MANE Select: NM_000440
dbSNP: rs578228152
Type: single nucleotide variant
Location: chr5:149884578 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 643: the pdease domain

Full PDE6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE6A p.Ala766Gly Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg236Leu Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg237Cys Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg237His Uncertain significance ★★ same condition
PDE6A p.Arg257Gln Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg267Cys Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg306Gly Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg554Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pde6a-p-ser643ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown